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Cell injury(1)

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Cell injury(1)

  1. 1. Cell Injury I – Cell Injury and Cell Death
  2. 2. Key Concepts • Normal cells have a fairly narrow range of function or steady state: Homeostasis • Excess physiologic or pathologic stress may force the cell to a new steady state: Adaptation • Too much stress exceeds the cell’s adaptive capacity: Injury
  3. 3. Key Concepts (cont’d) • Cell injury can be reversible or irreversible • Reversibility depends on the type, severity and duration of injury • Cell death is the result of irreversible injury
  4. 4. Cell Injury – General Mechanisms • Four very interrelated cell systems are particularly vulnerable to injury: – Membranes (cellular and organellar) – Aerobic respiration – Protein synthesis (enzymes, structural proteins, etc) – Genetic apparatus (e.g., DNA, RNA)
  5. 5. Cell Injury – General Mechanisms • Loss of calcium homeostasis • Defects in membrane permeability • ATP depletion • Oxygen and oxygen-derived free radicals
  6. 6. Causes of Cell Injury and Necrosis1. Hypoxia/Hypoxic Injury – Ischemia – Hypoxemia – Loss of oxygen carrying capacity 2. Free radical damage 3. Chemicals, drugs, toxins 4. Infections 5. Physical agents 6. Immunologic reactions 7. Genetic abnormalities 8. Nutritional imbalance
  7. 7. Cell injury See also Chap. 1, p. 14, Fig. 1-17
  8. 8. Mechanisms of injury See Ch. 1, p. 17, Fig. 1-21
  9. 9. Ischemic injury See also Ch. 1, p. 14, Fig. 1-17
  10. 10. Cell Injury • Membrane damage and loss of calcium homeostasis are most crucial • Some models of cell death suggest that a massive influx of calcium “causes” cell death • Too much cytoplasmic calcium: –Denatures proteins –Poisons mitochondria –Inhibits cellular enzymes
  11. 11. Calcium in cell injury See Ch. 1, p. 15, Fig. 1-19Effect of Increased Calcium
  12. 12. Reversible and irreversible injury See Ch. 1, p. 9, Fig. 1-9
  13. 13. Clinical Correlation • Injured membranes are leaky • Enzymes and other proteins that escape through the leaky membranes make their way to the bloodstream, where they can be measured in the serum
  14. 14. Examples of Free Radical Injury • Chemical (e.g., CCl4, acetaminophen) • Inflammation / Microbial killing • Irradiation (e.g., UV rays  skin cancer) • Oxygen (e.g., exposure to very high oxygen tension on ventilator) • Age-related changes
  15. 15. Mechanism of Free Radical Injury • Lipid peroxidation  damage to cellular and organellar membranes • Protein cross-linking and fragmentation due to oxidative modification of amino acids and proteins • DNA damage due to reactions of free radicals with thymine
  16. 16. Morphology of Cell Injury – Key Concept • Morphologic changes follow functional changes
  17. 17. Reversible Injury -- Morphology • Light microscopic changes –Cell swelling (a/k/a hydropic change) –Fatty change • Ultrastructural changes –Alterations of cell membrane –Swelling of and small amorphous deposits in mitochondria –Swelling of RER and detachment of ribosomes
  18. 18. Irreversible Injury -- Morphology• Light microscopic changes – Increased cytoplasmic eosinophilia (loss of RNA, which is more basophilic) – Cytoplasmic vacuolization – Nuclear chromatin clumping • Ultrastructural changes – Breaks in cellular and organellar membranes – Larger amorphous densities in mitochondria – Nuclear changes
  19. 19. Irreversible Injury – Nuclear Changes • Pyknosis –Nuclear shrinkage and increased basophilia • Karyorrhexis –Fragmentation of the pyknotic nucleus • Karyolysis –Fading of basophilia of chromatin
  20. 20. Karyolysis & karyorrhexis -- micro
  21. 21. Types of Cell Death • Apoptosis –Usually a regulated, controlled process –Plays a role in embryogenesis • Necrosis –Always pathologic – the result of irreversible injury –Numerous causes
  22. 22. Apoptosis • Involved in many processes, some physiologic, some pathologic – Programmed cell death during embryogenesis – Hormone-dependent involution of organs in the adult (e.g., thymus) – Cell deletion in proliferating cell populations – Cell death in tumors – Cell injury in some viral diseases (e.g., hepatitis)
  23. 23. Apoptosis – Morphologic Features • Cell shrinkage with increased cytoplasmic density • Chromatin condensation • Formation of cytoplasmic blebs and apoptotic bodies • Phagocytosis of apoptotic cells by adjacent healthy cells
  24. 24. Apoptosis Diagram Ch. 1, p. 6, Fig. 1-6
  25. 25. Types of Necrosis • Coagulative (most common) • Liquefactive • Caseous • Fat necrosis • Gangrenous necrosis
  26. 26. Coagulative Necrosis • Cell’s basic outline is preserved • Homogeneous, glassy eosinophilic appearance due to loss of cytoplasmic RNA (basophilic) and glycogen (granular) • Nucleus may show pyknosis, karyolysis or karyorrhexis
  27. 27. Renal infarct -- gross
  28. 28. Splenic infarcts -- gross
  29. 29. Infarcted bowel -- gross
  30. 30. Adrenal infarct -- Micro
  31. 31. 3 stages of coagulative necrosis (L to R) -- micro
  32. 32. Liquefactive Necrosis • Usually due to enzymatic dissolution of necrotic cells (usually due to release of proteolytic enzymes from neutrophils) • Most often seen in CNS and in abscesses
  33. 33. Lung abscesses (liquefactive necrosis) -- gross
  34. 34. Liver abscess -- micro
  35. 35. Liquefactive necrosis -- gross
  36. 36. Liquefactive necrosis of brain -- micro
  37. 37. Organizing liquefactive necrosis with cysts -- gross
  38. 38. Caseous Necrosis • Gross: Resembles cheese • Micro: Amorphous, granular eosinophilc material surrounded by a rim of inflammatory cells –No visible cell outlines – tissue architecture is obliterated • Usually seen in infections (esp. mycobacterial and fungal infections)
  39. 39. Caseous necrosis -- gross
  40. 40. Caseous -- gross
  41. 41. Extensive caseous necrosis -- gross
  42. 42. Enzymatic Fat Necrosis • Results from hydrolytic action of lipases on fat • Most often seen in and around the pancreas; can also be seen in other fatty areas of the body, usually due to trauma • Fatty acids released via hydrolysis react with calcium to form chalky white areas  “saponification”
  43. 43. Enzymatic fat necrosis of pancreas -- gross
  44. 44. Fat necrosis -- gross
  45. 45. Fat necrosis -- micro
  46. 46. Gangrenous Necrosis • Most often seen on extremities, usually due to trauma or physical injury • “Dry” gangrene – no bacterial superinfection; tissue appears dry • “Wet” gangrene – bacterial superinfection has occurred; tissue looks wet and liquefactive
  47. 47. Gangrene -- gross
  48. 48. Wet gangrene -- gross
  49. 49. Fibrinoid Necrosis • Usually seen in the walls of blood vessels (e.g., in vasculitides) • Glassy, eosinophilic fibrin-like material is deposited within the vascular walls

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